Oligodendrocytes (OLs) and the myelin they form are essential for normal brain function. Loss or dysfunction of these cells has been implicated in several diseases, from multiple sclerosis to psychiatric disorders such as schizophrenia and depression. Therefore, understanding the mechanisms that regulate OL and myelin development should provide insights into the pathogenesis of these diseases and possibly to the development of new therapeutic approaches. It has been proposed that the trophic factor neuregulin 1 (NRG1) and its receptors, the erbB receptor tyrosine kinases, regulate important aspects of OL development. OLs and their precursors (OPCs) express erbB receptors. NRG, which is produced by neurons, activates erbB receptors in OPCs and mature OLs in culture and has effects on their state of differentiation and proliferation in vitro. However, the roles of NRG1- erbB signaling in OL development and the mechanisms by which this occurs remain poorly understood. Recent studies suggest that the biological outcome of NRG1-erbB signaling in OPCs may depend on which NRG1 isoform is involved and which erbB receptor(s) is activated. We propose to test this possiblity using genetically modified mice and cells in tissue culture. The specific aims of this proposal are 1) to determine the roles of erbB signaling in OL development and myelination in vivo after birth. This will be achieved by analyzing the phenotypes of mice in which the function of all NRG1 receptors (erbB2, erbB3 and erbB4) is eliminated in cells of the OL lineage by expression of a dominant-negative erbB receptor, and mice in which OL expression of either erbB2 or erbB4 is eliminated by cell specific Cre/loxP recombination system, and 2) to determine the mechanisms by which NRG1-erbB signaling regulates OL development. We propose to study the effects of different NRG1 isoforms on OPC proliferation, survival, differentiation and gene expression. The experiments will also test if the manner in which the different NRG1 molecules are presented, either in cell-cell contact or as soluble factors, influences their bioactivities. The effects of activation of the different erbB receptors in OPCs will be tested by examining what happens to OPCs when the receptors are removed one at a time, or when different erbB receptor homo- and heterodimers are activated. We will also test the hypothesis that erbB4 regulates OPC development through a novel presenilin-dependent nuclear signaling pathway we have recently discovered.